Pleiotropic Anti-Angiogenic and Anti-Oncogenic Activities of the Novel Mithralog Demycarosyl-3D-ß-D-Digitoxosyl-Mithramycin SK (EC-8042)

Fernández-Guizán, Azahara; López‐Soto, Alejandro; Acebes-Huerta, Andrea; Huergo-Zapico, Leticia; Villa-Álvarez, Mónica; Núñez, Luz-Elena; Morís, Francisco; González, Segundo

doi:10.1371/journal.pone.0140786

Cited by 12 publications

(7 citation statements)

References 35 publications

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“…Recently, the new mithralog demycarosyl-3D-β-D-digitoxosyl-mithramycin SK (EC-8042; DIG-MSK) has been obtained and characterized [ 17 ]. As expected, EC-8042 preferentially binds GC-rich sequences, is a potent inhibitor of SP-driven gene expression and shows pleiotropic anti-angiogenic and anti-oncogenic activities [ 18 – 20 ]. EC-8042 altered the expression of cell cycle related genes resulting in cell cycle arrest and apoptosis in breast cancer cell lines [ 21 ].…”

Section: Introductionmentioning

confidence: 72%

Inhibition of SP1 by the mithramycin analog EC-8042 efficiently targets tumor initiating cells in sarcoma

et al. 2016

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Tumor initiating cells (TICs), responsible for tumor initiation, and cancer stem cells (CSCs), responsible for tumor expansion and propagation, are often resistant to chemotherapeutic agents. To find therapeutic targets against sarcoma initiating and propagating cells we used models of myxoid liposarcoma (MLS) and undifferentiated pleomorphic sarcoma (UPS) developed from human mesenchymal stromal/stem cells (hMSCs), which constitute the most likely cell-of-origin for sarcoma. We found that SP1-mediated transcription was among the most significantly altered signaling. To inhibit SP1 activity, we used EC-8042, a mithramycin (MTM) analog (mithralog) with enhanced anti-tumor activity and highly improved safety. EC-8042 inhibited the growth of TIC cultures, induced cell cycle arrest and apoptosis and upregulated the adipogenic factor CEBPα. SP1 knockdown was able to mimic the anti-proliferative effects induced by EC-8042. Importantly, EC-8042 was not recognized as a substrate by several ABC efflux pumps involved in drug resistance, and, opposite to the chemotherapeutic drug doxorubicin, repressed the expression of many genes responsible for the TIC/CSC phenotype, including SOX2, C-MYC, NOTCH1 and NFκB1. Accordingly, EC-8042, but not doxorubicin, efficiently reduced the survival of CSC-enriched tumorsphere sarcoma cultures. In vivo, EC-8042 induced a profound inhibition of tumor growth associated to a strong reduction of the mitotic index and the induction of adipogenic differentiation and senescence. Finally, EC-8042 reduced the ability of tumor cells to reinitiate tumor growth. These data suggest that EC-8042 could constitute an effective treatment against both TIC and CSC subpopulations in sarcoma.

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Section: Introductionmentioning

confidence: 72%

Inhibition of SP1 by the mithramycin analog EC-8042 efficiently targets tumor initiating cells in sarcoma

et al. 2016

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“…Mithramycin and additional analogs demonstrated rapid intracellular accumulation in OVCAR-3 cell lines [ 38 ]. The IC 50 values of mithramycin and related compounds were in the low-nanomolar range in OVCAR-3 cell cultures, induce cell arrest in G1 [ 70 ]. This finding raises the possibility of mithramycin or its analog as a potential treatment for chemotherapy-resistant ovarian cancer, particularly platinum-resistant cancer.…”

Section: Sp1mentioning

confidence: 99%

“…One of the most promising mithralogs, demycarosyl-3D-betat-D-digitoxosyl-mithramycin SK (MTM-DIG-MSK or EC-8042), has demonstrated retained anti-tumor properties, including in vitro ovarian cancer lines, but reduced in vitro toxicity in fibroblasts and mononuclear blood cells, compared to mithramycin [ 37 , 40 , 70 , 82 ]. Mithramycin and EC-8042 reduced the viability and invasiveness of malignant melanoma cell lines [ 85 ].…”

Section: Development Of Mithramycin Analoguesmentioning

confidence: 99%

“…Mithramycin analogs also demonstrated efficacy in pre-clinical ovarian studies. EC-8042 displayed significant anti-tumor activity against ovarian cancer cell lines with significantly lower toxicity to fibroblasts and peripheral blood cells compared to mithramycin; while strongly inhibiting Sp1 transcription and reduction in several genes implicated in tumorigenesis including VEGF, BRCA2, cMyc, and src [ 38 , 70 ]. In one of the most detailed studies involving ovarian cancer and MTM analogs, MTM-SDK and MTM-SK, demonstrated considerable inhibition of Sp1 dependent transcription in vitro.…”

Section: Development Of Mithramycin Analoguesmentioning

confidence: 99%

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Mithramycin and Analogs for Overcoming Cisplatin Resistance in Ovarian Cancer

et al. 2021

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Ovarian cancer is a highly deadly malignancy in which recurrence is considered incurable. Resistance to platinum-based chemotherapy bodes a particularly abysmal prognosis, underscoring the need for novel therapeutic agents and strategies. The use of mithramycin, an antineoplastic antibiotic, has been previously limited by its narrow therapeutic window. Recent advances in semisynthetic methods have led to mithramycin analogs with improved pharmacological profiles. Mithramycin inhibits the activity of the transcription factor Sp1, which is closely linked with ovarian tumorigenesis and platinum-resistance. This article summarizes recent clinical developments related to mithramycin and postulates a role for the use of mithramycin, or its analog, in the treatment of platinum-resistant ovarian cancer.

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“…In a functional study, it was found that two new analogs of MTA, namely MTMSDK and MTM-SK, hindered the growth of OC cells in xenografts via inhibition of Sp1-based transcription [87]. Another efficient analog of MTA is demycarosyl-3D-ß-D-digitoxosyl-mithramycin SK (DIG-MSK), as it can inhibit Sp1-mediated transcription, mRNA expression, and various other genes regulated by Sp1 that have a pivotal role in OC, like VEGFA, BCL2L1 (Bcl-2-like 1; Bcl-XL), human telomerase Reverse Transcriptase (hTERT), BRCA2, and MYC [88]. Similar to this study, Vizcaino et al also observed that DIG-MSK can downregulate the binding of Sp1 to pro-oncogenes in OC cells [89].…”

Section: Sp1 As a Therapeutic Target In Ocmentioning

confidence: 99%

Understanding the Role of the Transcription Factor Sp1 in Ovarian Cancer: from Theory to Practice

Vellingiri

Iyer

Subramaniam

et al. 2020

IJMS

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Ovarian cancer (OC) is one of the deadliest cancers among women contributing to high risk of mortality, mainly owing to delayed detection. There is no specific biomarker for its detection in early stages. However, recent findings show that over-expression of specificity protein 1 (Sp1) is involved in many OC cases. The ubiquitous transcription of Sp1 apparently mediates the maintenance of normal and cancerous biological processes such as cell growth, differentiation, angiogenesis, apoptosis, cellular reprogramming and tumorigenesis. Sp1 exerts its effects on cellular genes containing putative GC-rich Sp1-binding site in their promoters. A better understanding of the mechanisms underlying Sp1 transcription factor (TF) regulation and functions in OC tumorigenesis could help identify novel prognostic markers, to target cancer stem cells (CSCs) by following cellular reprogramming and enable the development of novel therapies for future generations. In this review, we address the structure, function, and biology of Sp1 in normal and cancer cells, underpinning the involvement of Sp1 in OC tumorigenesis. In addition, we have highlighted the influence of Sp1 TF in cellular reprogramming of iPSCs and how it plays a role in controlling CSCs. This review highlights the drugs targeting Sp1 and their action on cancer cells. In conclusion, we predict that research in this direction will be highly beneficial for OC treatment, and chemotherapeutic drugs targeting Sp1 will emerge as a promising therapy for OC. common reproductive cancer among women in India [2]. Although OC is a single disease, its clinical pathway is mostly intercalated by other tumor types having different prognosis stages, morphologies, and molecular and epigenetic backgrounds [3]. Presently, there are no early-stage treatment options for OC since the early symptoms cannot be comprehended. Due to high prevalence and the continuously rising incidence, OC poses a major threat to personal health as well as the health care system [1]. Despite ongoing efforts to detect OC, specific diagnostic biomarkers are yet to be identified [4]. It is evident that transcription factors (TFs) play a pivotal role in the regulation of cellular functions, including cell activation, repression, and alteration of gene expression. Any dysfunctional activation or inactivation of TFs may result in cellular induction of tumorigenesis [4]. Mutations in cancer is caused due to changes in various proteins functions and transcriptions factors which are controlling the protein, thus changing the phenotypes in human [5]. Bookmarking of mitosis constitutes a mechanism that transmits transcriptional patterns by cell division. Bookmarking factors, comprising a subset of TFs, and multiple histone modifications retained in mitotic chromatin facilitate reactivation of transcription in the early G1 phase [6]. It is possible that Sp1 phosphorylation may change its interaction with other transcription factors [7]. Specificity protein 1 (Sp1) is one such ubiquitous and multifunctional TF from the Sp/Kru...

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Pleiotropic Anti-Angiogenic and Anti-Oncogenic Activities of the Novel Mithralog Demycarosyl-3D-ß-D-Digitoxosyl-Mithramycin SK (EC-8042)

Cited by 12 publications

References 35 publications

Inhibition of SP1 by the mithramycin analog EC-8042 efficiently targets tumor initiating cells in sarcoma

Inhibition of SP1 by the mithramycin analog EC-8042 efficiently targets tumor initiating cells in sarcoma

Mithramycin and Analogs for Overcoming Cisplatin Resistance in Ovarian Cancer

Understanding the Role of the Transcription Factor Sp1 in Ovarian Cancer: from Theory to Practice

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